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The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p

Background and hypothesisChildren exposed to socioenvironmental adversities (eg, urbanicity, pollution, neighborhood deprivation, crime, and family disadvantage) are more likely to subsequently develop subclinical psychotic experiences during adolescence (eg, hearing voices, paranoia). However, the pathways through which this occurs have not been previously investigated. We hypothesized that cognitive ability and inflammation would partly explain this association.Study designData were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994-1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences.Study resultsHigher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses.ConclusionsCognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.

ObjectiveTo explore differences in regional cortical morphometric structure between adolescents at risk for depression or with current depression.MethodsWe analyzed cross-sectional structural neuroimaging data from a sample of 150 Brazilian adolescents classified as low-risk (n=50) or high-risk for depression (n=50) or with current depression (n=50) through a vertex-based approach with measurements of cortical volume, surface area and thickness. Differences between groups in subcortical volumes and in the organization of networks of structural covariance were also explored.ResultsNo significant differences in brain structure between groups were observed in whole-brain vertex-wise cortical volume, surface area or thickness. Also, no significant differences in subcortical volume were observed between risk groups. In relation to the structural covariance network, there was an indication of an increase in the hippocampus betweenness centrality index in the high-risk group network compared to the low-risk and current depression group networks. However, this result was only statistically significant when applying false discovery rate correction for nodes within the affective network.ConclusionIn an adolescent sample recruited using an empirically based composite risk score, no major differences in brain structure were detected according to the risk and presence of depression.

Adolescents comprise one fourth of the world's population, with about 90% of them living in low- and middle-income countries (LMICs). The incidence of depression markedly increases during adolescence, making the disorder a leading cause of disease-related disability in this age group. However, most research on adolescent depression has been performed in high-income countries (HICs). To ascertain the extent to which this disparity operates in neuroimaging research, a systematic review of the literature was performed. A total of 148 studies were identified, with neuroimaging data available for 4,729 adolescents with depression. When stratified by income group, 122 (82%) studies originated from HICs, while 26 (18%) were conducted in LMICs, for a total of 3,705 and 1,024 adolescents with depression respectively. A positive Spearman rank correlation was observed between country per capita income and sample size (rs=0.673, p = 0.023). Our results support the previous reports showing a large disparity between the number of studies and the adolescent population per world region. Future research comparing neuroimaging findings across populations from HICs and LMICs may provide unique insights to enhance our understanding of the neurobiological processes underlying the development of depression.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS). Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers. Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample. Results: A total of 7,720 adolescents aged 14-16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group. Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.

Background: Students often simultaneously deal with shifting support networks, stressful life changes and psychological distress which may affect academic achievement. Methods: 285 students completed the General Health Questionnaire (GHQ-12) to assess depression and the Computerized Life Events Assessment Record (CLEAR), to establish life events and supportive relationships. Module grades were used to measure academic achievement. A general linear model was used with student grade as the dependent variable and life events, depression and supportive relationships as independent variables. Confounding variables included age and sex. Results: A three-way interaction between life events, depression and lack of supportive relationships was found. It indicated the performance of depressed students depended on whether they had supportive relationships and that this interaction also depended on whether they had experienced a life event in the past year. Conclusions: Universities need to provide more support to students with life stress as they transition into university life.

The present study used quantitative and qualitative methods to explore how lonely young people are seen from others' perspectives, in terms of their personality, behavior, and life circumstances. Data were drawn from the Environmental Risk Longitudinal Twin Study, a cohort of 2,232 individuals born in the U.K. in the mid-1990s. When participants were aged 18, they provided self-reports of loneliness, and informant ratings of loneliness were provided by interviewers, as well as participants' parents and siblings. Interviewers further provided Big Five personality ratings and detailed written notes in which they documented their perceptions of the participants and their reflections on the content of the interview. In the quantitative section of the article, regression analyses were used to examine the perceptibility of loneliness and how participants' loneliness related to their perceived personality traits. The informant ratings of participants' loneliness showed good agreement with self-reports. Furthermore, loneliness was associated with lower perceived conscientiousness, agreeableness, and extroversion and higher perceived neuroticism. Within-twin pair analyses indicated that these associations were partly explained by common underlying genetic influences. In the qualitative section of the study, the loneliest 5% of study participants (N = 108) were selected, and thematic analysis was applied to the study interviewers' notes about those participants. Three themes were identified and named: "uncomfortable in own skin," "clustering of risk," and "difficulties accessing social resources." These results add depth to the current conceptualization of loneliness and emphasize the complexity and intersectional nature of the circumstances severely lonely young adults live in.

Children from lower-income households are at increased risk for poor health, educational failure, and behavioral problems. This social gradient is one of the most reproduced findings in health and social science. How people view their position in social hierarchies also signals poor health. However, when adolescents' views of their social position begin to independently relate to well-being is currently unknown. A cotwin design was leveraged to test whether adolescents with identical family backgrounds, but who viewed their family's social status as higher than their same-aged and sex sibling, experienced better well-being in early and late adolescence. Participants were members of the Environmental Risk Longitudinal Twin Study, a representative cohort of British twins (n = 2,232) followed across the first 2 decades of life. By late adolescence, perceptions of subjective family social status (SFSS) robustly correlated with multiple indicators of health and well-being, including depression; anxiety; conduct problems; marijuana use; optimism; not in education, employment, or training (NEET) status; and crime. Findings held controlling for objective socioeconomic status both statistically and by cotwin design after accounting for measures of childhood intelligence (IQ), negative affect, and prior mental health risk and when self-report, informant report, and administrative data were used. Little support was found for the biological embedding of adolescents' perceptions of familial social status as indexed by inflammatory biomarkers or cognitive tests in late adolescence or for SFSS in early adolescence as a robust correlate of well-being or predictor of future problems. Future experimental studies are required to test whether altering adolescents' subjective social status will lead to improved well-being and social mobility.

BackgroundDepression is a leading contributor to disability-adjusted life-years because of early onset and chronicity throughout the lifecycle. It is crucial to identify early predictors of depression among adolescents and young people to effectively target prevention. A gap in the literature is a comprehensive systematic review of predictors of depression among adolescents around the globe, especially in low- and middle-income countries LMICs. This review aims to identify evidence for biological, psychological, and contextual risk factors for the development of depression among adolescents and young adults (10-24 years of age) in high-income countries (HICs) and LMICs, ultimately contributing to (a) identification of potential mechanisms underlying depression development, (b) selection of common risk and protective factors as targets for detection, and (c) refinement of risk models that can be evaluated through existing cohorts in HICs and LMICs.MethodsThis review will follow the Population, Exposure, Comparison, Outcome (PI(E)CO) model and adheres to the PRISMA-P guidelines. A search strategy was developed by a multidisciplinary research consortium. Seven databases (MEDLINE via Ovid, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, Global Health) will be searched to identify articles. Independent raters will screen and retrieve articles for inclusion, conduct quality ratings, and extract data. The Systematic Assessment of Quality in Observational Research adapted for Cultural Psychiatry Epidemiology (SAQOR-CPE) will be used to assess quality of observational studies. We will assess for publication bias using funnel plots and statistical methods. We will use narrative synthesis to present results, addressing the study's objectives following the Cochrane Handbook guidelines. Meta-analyses will be used to report summary statistics for association of risk factors with development of depression.DiscussionThis systematic review will summarize evidence-based research that examines the psychological, biological, and contextual factors contributing to the onset of depression in adolescents across the globe. Results will support the development of a model that can be evaluated in existing cohorts around the world.Systematic review registrationPROSPERO registration CRD42018103973 .

In this study, we investigated associations between the characteristics of the neighborhoods in which young adults live and their feelings of loneliness, using data from different sources. Participants were drawn from the Environmental Risk Longitudinal Twin Study. Loneliness was measured via self-reports at ages 12 and 18 years and also by interviewer ratings at age 18. Neighborhood characteristics were assessed between the ages of 12 and 18 via government data, systematic social observations, a resident survey, and participants' self-reports. Greater loneliness was associated with perceptions of lower collective efficacy and greater neighborhood disorder but not with more objective measures of neighborhood characteristics. Lonelier individuals perceived the collective efficacy of their neighborhoods to be lower than did their less lonely siblings who lived at the same address. These findings suggest that feelings of loneliness are associated with negatively biased perceptions of neighborhood characteristics, which may have implications for lonely individuals' likelihood of escaping loneliness.

Air pollution is a worldwide environmental health issue. Increasingly, reports suggest that poor air quality may be associated with mental health problems, but these studies often use global measures and rarely focus on early development when psychopathology commonly emerges. To address this, we combined high-resolution air pollution exposure estimates and prospectively-collected phenotypic data to explore concurrent and longitudinal associations between air pollutants of major concern in urban areas and mental health problems in childhood and adolescence. Exploratory analyses were conducted on 284 London-based children from the Environmental Risk (E-Risk) Longitudinal Twin Study. Exposure to annualized PM2.5 and NO2 concentrations was estimated at address-level when children were aged 12. Symptoms of anxiety, depression, conduct disorder, and attention-deficit hyperactivity disorder were assessed at ages 12 and 18. Psychiatric diagnoses were ascertained from interviews with the participants at age 18. We found no associations between age-12 pollution exposure and concurrent mental health problems. However, age-12 pollution estimates were significantly associated with increased odds of major depressive disorder at age 18, even after controlling for common risk factors. This study demonstrates the potential utility of incorporating high-resolution pollution estimates into large epidemiological cohorts to robustly investigate associations between air pollution and youth mental health.

BackgroundThe aim of this study was to build a detailed, integrative profile of the correlates of young adults' feelings of loneliness, in terms of their current health and functioning and their childhood experiences and circumstances.MethodsData were drawn from the Environmental Risk Longitudinal Twin Study, a birth cohort of 2232 individuals born in England and Wales in 1994 and 1995. Loneliness was measured when participants were aged 18. Regression analyses were used to test concurrent associations between loneliness and health and functioning in young adulthood. Longitudinal analyses were conducted to examine childhood factors associated with young adult loneliness.ResultsLonelier young adults were more likely to experience mental health problems, to engage in physical health risk behaviours, and to use more negative strategies to cope with stress. They were less confident in their employment prospects and were more likely to be out of work. Lonelier young adults were, as children, more likely to have had mental health difficulties and to have experienced bullying and social isolation. Loneliness was evenly distributed across genders and socioeconomic backgrounds.ConclusionsYoung adults' experience of loneliness co-occurs with a diverse range of problems, with potential implications for health in later life. The findings underscore the importance of early intervention to prevent lonely young adults from being trapped in loneliness as they age.

Background During the last decades, an abundance of studies has investigated childhood adversity in relation to psychosis. This systematic review critically examines the methodologies employed to investigate childhood adversity in psychosis over the past decade, including operational definitions, measurement tools and characteristics, and psychometric properties of instruments used in these studies. Study Design This systematic review followed the PRISMA guidelines (registration number CRD42022307096), and the search used the following electronic databases: PsychINFO, SCOPUS, Web of Science, African Index Medicus (AIM), LILACS, CINAHL, EMBASE, and MEDLINE. The search included variations and combinations of the terms targeting childhood adversity and psychosis. Study Results Out of 585 identified studies published between 2010 and 2023, 341 employed a validated instrument to investigate childhood adversity. Our findings show "childhood trauma" being the most frequently examined construct, followed by "child maltreatment" or "child abuse." The short version of the Childhood Trauma Questionnaire was the dominant instrument. Physical abuse, emotional abuse, and sexual abuse were most frequently investigated, and indeed the field appears generally to focus on child abuse and neglect over other adversities. Significant psychometric heterogeneity was observed in the selection and summarization of instrument items, with only 59% of studies documenting original psychometric validation and 22% reporting reliability in their datasets. Conclusion This review highlights substantial methodological heterogeneity in the field, pointing out biases in the research on childhood adversity and psychosis. These findings underline the need for standardized definitions and high-quality measurement tools to enhance the validity of future research in this area. [ABSTRACT FROM AUTHOR]

Objectives: Research indicates psychologists typically lack subjective understanding of voice hearing. Voice hearing simulation training has potential to improve understanding, empathy and confidence among clinicians, but psychologists have had limited input into its development. This study investigated psychologists' and a psychotherapist's clinical experience of working with people who hear voices and their views and recommendations for voice hearing simulation training. Design: This was a qualitative study. Methods: Clinical psychologists and one psychotherapist (N = 17) participated in semi‐structured interviews. Thematic analysis was used to analyse transcribed data. Results: The Clinical Experience theme comprised of subthemes Barriers to engagement, Diversity of voice hearing experiences, Lack of subjective understanding, Curiosity about voice hearing, Empathy for voice hearers, Using personal experiences to relate to voices, Clinical experience increases knowledge, Importance of supervision and colleague's support, Benefits of experiential training, Limited training in non‐psychosis settings and Clinical experience increases confidence. The Views on Voice Hearing Simulation Training theme comprised of subthemes Improves subjective understanding, Concern about distress, Discomfort as a strength of voice hearing simulations, Artificiality of simulation, Increases empathy and Over‐estimation of understanding. The Recommendations theme comprised of subthemes Discuss artificiality, Co‐production, Promote voice diversity, Support staff and Maximise inclusivity. Conclusions: Findings indicate that clinical experience improves psychologists' confidence and knowledge, yet participants reported a lack of subjective understanding of voice hearing. Co‐produced simulation training between individuals who hear voices and clinicians was anticipated to improve subjective understanding, empathy and therapeutic relationships, which could support a range of staff and improve quality of care delivered. [ABSTRACT FROM AUTHOR]

ObjectivesTo test whether childhood maltreatment was a predictor of (1) having low educational qualifications and (2) not being in education, employment, or training among young adults in the United Kingdom today.MethodsParticipants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK cohort of 2232 twins born in 1994 to 1995. Mothers reported on child maltreatment when participants were aged 5, 7, 10, and 12 years. Participants were interviewed about their vocational status at age 18 years.ResultsThe unadjusted odds of having low educational qualifications or of not being in education, employment, or training at age 18 years were more than 2 times greater for young people with a childhood history of maltreatment versus those without. These associations were reduced after adjustments for individual and family characteristics. Youths who reported having a supportive adult in their lives had better education outcomes than did youths who had less support.ConclusionsCloser collaboration between the child welfare and education systems is warranted to improve vocational outcomes for maltreated youths.

ObjectiveDNA methylation has been proposed as an epigenetic mechanism by which early-life experiences become "embedded" in the genome and alter transcriptional processes to compromise health. The authors sought to investigate whether early-life victimization stress is associated with genome-wide DNA methylation.MethodThe authors tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).ResultsEpigenome-wide analyses of polyvictimization across childhood and adolescence revealed few significant associations with DNA methylation in peripheral blood at age 18, but these analyses were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimization revealed sparse associations with DNA methylation that did not replicate across different operationalizations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes.ConclusionsFindings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimized young people. We need to come to terms with the possibility that epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.

PurposeIt is well-established that victims and offenders are often the same people, a phenomenon known as the victim-offender overlap, but the developmental nature of this overlap remains uncertain. In this study, we drew from a developmental theoretical framework to test effects of genetics, individual characteristics, and routine-activity-based risks. Drawing from developmental literature, we additionally tested the effect of an accumulation of adverse childhood experiences (ACEs).MethodsData came from the Environmental Risk (E-Risk) Study, a representative UK birth cohort of 2232 twins born in 1994-1995 and followed to age 18 (with 93% retention). Crime victimization and offending were assessed through self-reports at age 18 (but findings replicated using crime records). We used the classical twin study method to decompose variance in the victim-offender overlap into genetic and environmental components. We used logistic regression to test the effects of childhood risk factors.ResultsIn contrast to past twin studies, we found that environment (as well as genes) contributed to the victim-offender overlap. Our logistic regression results showed that childhood low self-control and childhood antisocial behavior nearly doubled the odds of becoming a victim-offender, compared to a victim-only or an offender-only. Each additional ACE increased the odds of becoming a victim-offender, compared to a victim-only or an offender-only, by approximately 12%, pointing to the importance of cumulative childhood adversity.ConclusionsThis study showed that the victim-offender overlap is, at least partially, developmental in nature and predictable from personal childhood characteristics and an accumulation of many adverse childhood experiences.

BackgroundLittle is known about the impact of urbanicity, adverse neighborhood conditions and violent crime victimization on the emergence of adolescent psychotic experiences.MethodsParticipants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins who were interviewed about adolescent psychotic experiences at age 18. Urbanicity, neighborhood characteristics, and personal victimization by violent crime were measured during childhood and adolescence via geocoded census data, surveys of over 5000 immediate neighbors of the E-Risk participants, and interviews with participants themselves.ResultsAdolescents raised in urban vs rural neighborhoods were significantly more likely to have psychotic experiences (OR = 1.67, 95% CI = 1.21-2.30, P = .002). This association remained significant after considering potential confounders including family socioeconomic status, family psychiatric history, and adolescent substance problems (OR = 1.43, 95% CI = 1.01-2.03, P = .042), but became nonsignificant after considering adverse social conditions in urban neighborhoods such as low social cohesion and high neighborhood disorder (OR = 1.35, 95% CI = 0.94-1.92, P = .102). The combined association of adverse neighborhood social conditions and personal crime victimization with adolescent psychotic experiences (adjusted OR = 4.86, 95% CI = 3.28-7.20, P < .001) was substantially greater than for either exposure alone, highlighting a potential interaction between neighborhood conditions and crime victimization (interaction contrast ratio = 1.81, 95% CI = -0.03 to 3.65) that was significant at the P = .054 level.ConclusionsCumulative effects of adverse neighborhood social conditions and personal victimization by violent crime during upbringing partly explain why adolescents in urban settings are more likely to report psychotic experiences. Early intervention efforts for psychosis could be targeted towards victimized youth living in urban and socially adverse neighborhoods.

Adolescent psychotic experiences increase risk for schizophrenia and other severe psychopathology in adulthood. Converging evidence implicates urban and adverse neighborhood conditions in the etiology of adolescent psychotic experiences, but the role of young people's personal perceptions of disorder (i.e., physical and social signs of threat) in their neighborhood is unknown. This was examined using data from the Environmental Risk Longitudinal Twin Study, a nationally representative birth cohort of 2,232 British twins. Participants were interviewed at age 18 about psychotic phenomena and perceptions of disorder in the neighborhood. Multilevel, longitudinal, and genetically sensitive analyses investigated the association between perceptions of neighborhood disorder and adolescent psychotic experiences. Adolescents who perceived higher levels of neighborhood disorder were significantly more likely to have psychotic experiences, even after accounting for objectively/independently measured levels of crime and disorder, neighborhood- and family-level socioeconomic status, family psychiatric history, adolescent substance and mood problems, and childhood psychotic symptoms: odds ratio = 1.62, 95% confidence interval [1.27, 2.05], p < .001. The phenotypic overlap between adolescent psychotic experiences and perceptions of neighborhood disorder was explained by overlapping common environmental influences, rC = .88, 95% confidence interval [0.26, 1.00]. Findings suggest that early psychological interventions to prevent adolescent psychotic experiences should explore the role of young people's (potentially modifiable) perceptions of threatening neighborhood conditions.

Background Growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-term pre-pandemic psychological distress trajectories were disrupted during the pandemic, and whether these changes have been different across cohorts and by sex. Methods and findings We used data from three nationally representative birth cohorts comprising all people born in Great Britain in a single week of 1946 (National Survey of Health and Development, NSHD), 1958 (National Child Development Study, NCDS), or 1970 (British Cohort Study, BCS70). The follow-up data used spanned 39 years in NSHD (1982 to 2021), 40 years in NCDS (1981 to 2001), and 25 years in BCS70 (1996 to 2021). We used psychological distress factor scores, as measured by validated self-reported questionnaires (NSHD: Present State Examination, Psychiatric Symptoms Frequency, and 28- and 12-item versions of General Health Questionnaire; NCDS and BCS70: Malaise Inventory; all: 2-item versions of Generalized Anxiety Disorder scale and Patient Health Questionnaire). We used a multilevel growth curve modelling approach to model the trajectories of distress across cohorts and sexes and obtained estimates of the differences between the distress levels observed during the pandemic and those observed at the most recent pre-pandemic assessment and at the peak in the cohort-specific pre-pandemic distress trajectory, located at midlife. We further analysed whether pre-existing cohort and sex inequalities had changed with the pandemic onset using a difference-in-differences (DiD) approach. The analytic sample included 16,389 participants. By September/October 2020, distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts (standardised mean differences [SMD] and 95% confidence intervals of SMD.sub.NSHD,pre-peak = -0.02 [-0.07, 0.04], SMD.sub.NCDS,pre-peak = 0.05 [0.02, 0.07], and SMD.sub.BCS70,pre-peak = 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively). Increases in distress were larger among women than men, widening pre-existing sex inequalities (DiD and 95% confidence intervals of DiD.sub.NSHD,sex,pre-peak = 0.17 [0.06, 0.28], DiD.sub.NCDS,sex,pre-peak = 0.11 [0.07, 0.16], and DiD.sub.BCS70,sex,pre-peak = 0.11 [0.05, 0.16] when comparing sex inequalities in the pre-pandemic peak in midlife to those observed by September/October 2020). As expected in cohort designs, our study suffered from high proportions of attrition with respect to the original samples. Although we used non-response weights to restore sample representativeness to the target populations (those born in the United Kingdom in 1946, 1958, and 1970, alive and residing in the UK), results may not be generalisable to other sections within the UK population (e.g., migrants and ethnic minority groups) and countries different than the UK. Conclusions Pre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems., Author(s): Darío Moreno-Agostino 1,2,*, Helen L. Fisher 2,3, Alissa Goodman 1, Stephani L. Hatch 2,4, Craig Morgan 2,5, Marcus Richards 6, Jayati Das-Munshi 2,4,7, George B. Ploubidis 1,2 Introduction Mental [...]